20060331舒利迭疗效及安全性

舒利迭的疗效及药物安全性梁永杰2006年3月31日哮喘的本质-气道炎症平滑肌上皮肺泡健康人的气道上皮受损，脱落炎症，水肿粘液，血浆渗出哮喘病人的气道平滑肌痉挛治疗策略：抗炎+解痉联合治疗HeliumHe3MRIinapatientwithmoderatelypersistentasthmawhounderwentimagingtwice:Thisfirstimagewasobtainedbeforetreatmentwithaninhaledbronchodilator.Multipledarkareasofwedge-shapedventilationdefectsimproveorresolveafteralbuteroltreatment.二类平喘药物Twotypesofmedicationhelpcontrolasthma解痉平喘药1.β2受体激动剂2.抗胆碱药3.茶碱类4.白三烯受体拮抗剂顺尔宁抗炎平喘药1.糖皮质激素2.色甘酸钠哮喘的药物治疗吸入型糖皮质激素–二丙酸倍氯米松(BDP)–布地奈德(BUD)–丙酸氟替卡松(FP)吸入长效2激动剂–沙美特罗(Salmeterol)–福莫特罗(Formoterol)其他–口服长效2激动剂（班布特罗、丙卡特罗）–抗白三烯药物–甲基黄嘌呤–色甘酸钠/尼多克罗米–全身激素减量疗法速效吸入型2受体激动剂短效口服2受体激动剂（沙丁胺醇、特布他林）抗胆碱能药物甲基黄嘌呤全身性皮质激素快速缓解用药长期控制用药全球哮喘防治创议(GINA2002年)全面控制中、重度哮喘加吸入长效ß2激动剂加倍剂量吸入激素加缓释茶碱加抗白三烯药物传统认为：吸入激素GINA2002HOOCOC2H5C=0COSCH2FOCH3FF吸入长效2受体激动剂-沙美特罗CHCH2NHCH2OHOHOOHCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2吸入激素--丙酸氟替卡松(辅舒酮)舒利迭主要成分体现治疗策略：抗炎+解痉联合治疗05101520253035036912151821时间(周)沙美特罗50gbid+BDP200gbidBDP500gbid**************p0.05,**p0.01,***p0.001vsBDPGreeningetal.Lancet1994对轻-中度哮喘，沙美特罗加吸入激素的效果优于单纯增加吸入激素剂量和基础值比较，清晨PEF变化均值(L/min)-10010304020有利于加用沙美特罗-30-20-40有利于单纯增加吸入激素剂量治疗差异(%)Shrewsburyetal.BMJ2000IndGreeningWoolcockKelsenMurrayKalbergCondemi总效果随机效果ICS,inhaledcorticosteroidValuesaremeanpercentagewith95%confidenceintervals沙美特罗和吸入激素联用6月使哮喘病人的无症状日增加JenkinsCetal.RespirMed2000;94(7):715-23.舒利迭50/250bid改善肺功能明显优于3倍剂量的布地奈德都保组800mcgbid疗效差异***p0.001舒利迭®50/250mcgbdN=180布地奈德(800mcgbd)N=173清晨PEF的均值(L/min)***340360370380390400410420350基线治疗1-4周治疗5-8周治疗9-12周治疗13-24周治疗1-24周************舒利迭50/250bid改善哮喘患者的生活质量优于3倍剂量的布地奈德都保组800mcgbidJuniperetal.EurRespirJ1999;14(Suppl30):370sP2460.1.5舒利迭®50/250mcgbid(n=73)p=0.002布地奈德800mcgbid(n=71)p=0.026p=0.001p=0.006p=0.0171.00.5AQLQ总积分活动受限哮喘症状情绪变化环境刺激生活质量计分的平均改变051015202530351-45-89-1213-1617-2021-24周Salmeterol50g+FP100gbidFP250gbid*************p0.014***p0.001舒利迭比单用吸入激素显著增加哮喘无症状日Condemietal.AnnAllergyAsthmaImmunol1999FP,fluticasonepropionateICS,inhaledcorticosteroid无症状日增加的百分比%N=447*p0.001vs丙酸氟替卡松+孟鲁司特舒利迭®50/100丙酸氟替卡松+孟鲁司特20181516121086420基线值FEV1较基线的变化百分比治疗周研究终点*14812****NelsonHS,BusseWW,KerwinEetal.Fluticasonepropionate/salmeterolcombinationprovidesmoreeffectiveasthmacontrolthanlow-doseinhaledcorticosteroidplusmontelukast.JAllergyClinImmunol2000;106:1088-1095舒利迭50/100bid在改善FEV1方面优于(氟替卡松+孟鲁司特)Lundbäcketal.EurRespirJ2002舒利迭比单用吸入激素减少每年恶化0.3391.5560.696p0.0012.52.01.51.00.50氟替卡松FP250mcgbd舒利迭(沙美特罗/氟替卡松)50/250mcgbd沙美特罗50mcgbdp=0.001p0.001N=95N=92N=95每个病人每年平均恶化数长效β2激动剂和吸入激素联用：对肺功能的作用是叠加还是协同？Kavuruetal.JAllergyClinImmunol2000-30-20103070天0和基础值比较清晨PEF变化均值(L/min)721426384沙美特罗安慰剂5040200-106014355677284970舒利迭(沙美特罗/氟替卡松)50/100FP100CBA1438195(13.5%)1.39%2.22%2.08%1.53%1%患者数药物相关的不良反应头痛声音嘶哑/发声困难口咽部念珠菌感染咽喉刺痛咳嗽61887(14.1%)1.78%1.94%2.26%1.62%1%1809(5.0%)01%01%1%67689(13.2%)1%1.63%1.33%1.92%1.18%1755(2.8%)001.14%1%0舒利迭沙美特罗+氟替卡松沙美特罗氟替卡松安慰剂发生率1%的不良反应IncidenceofadverseeventslowerinsalmeterolandplacebogroupsthanSeretidegroupduetoshorterexposuretime(manypatientswithdrawninfirsttwostudyarms)Kavuruetal.JAllergyClinImmunol2000;Shapiroetal.AmJRespirCritCareMed2000;Batemanetal.ClinDrugInvest1998;Chapmanetal.CanRespirJ1999;Aubieretal.RespirMed1999;Batemanetal.RespirMed2001;vanNoordetal.ClinDrugInvest2001舒利迭研究中所报道的成人和少年患者的药物相关的不良反应Similaracrossallstrata舒利迭(n=102)FP(n=92)GOALStudy大部分患者维持正常皮质醇功能基线偏低正常偏高偏低正常偏高终点偏低080160正常57527861偏高020010治疗时期：52周GOAL研究：以完全控制为目标1年后对24小时尿皮质醇几乎无影响Nathanetal.AmJRespirCritCareMed20010100200300400500QTcinterval(msec)TreatmentPeriod舒利迭50/100gbid氟替卡松100gbid沙美特罗50gbid安慰剂筛选期第1天（用药前）第1天（用药后）12周（用药前）12周（用药后）舒利迭(50/250g):不影响心血管参数Ringdaletal,200301％2％3％4％5％舒利迭50/100µgbid氟替卡松100µgbid+孟鲁斯特10mgqd治疗12周后的口腔念珠菌感染的患者(%)NS舒利迭不增加口腔念珠菌感染舒利迭成分之一：丙酸氟替卡松：对人体肺部糖皮质激素受体选择性和亲和力最高1具有极强而持久的局部抗炎活性2，3丙酸氟替卡松生物利用度最小，血浆蛋白结合率高，长期应用系统副作用小41.JohnsonMJ.JAllergyClinImmunol19982.HoggerPetal.Steroids1994;59:597-6023.McKenzieAW.ArchDermatol1962;86:611-44.H.Derendorf.RespirMed1997;91(SupplA):22-28几种吸入激素的生物利用度比较1ProductInformation.2Daley-Yatesetal.BrJClinPharmacol2001;51:400-409.3LeachC.EurRespirJ1998;12:1346-1353.4Estimatedfromavailablevalues.5Chaplinetal.ClinPharmacolTher1980;27:402-413.6Derendorfetal.JClinPharmacol1995;35:302-305.7Argentietal.JClinPharmacol1999;39:695-702.ICS口服吸入合计丙酸氟替卡松准纳器1%118%118%1布地奈德6%-13%134%139%1丙酸倍氯米松CFC26%236%2~62%2丙酸倍氯米松HFA6%360%366%3氟尼缩松20.1%5~20%440%1曲安奈德10.6%7-22.5%6~4.44-10.4%7~25%7-32%4氟替卡松（辅舒酮）：药理学特点优于布地奈德3.JohnsonM.,Pharmacodynamicsandpharmacokineticsofinhaledglucocorticoids.JAllergyClinImmunol1996;97:169-1761.JohnsonM.,DevelopmentofFluticasonepropionateandcomparisonwithotherinhaledcorticosteroids,JAllergyClin.Immunol.1998;101:S434-S4392.DerendorfH.,Pharmacokineticandpharmacodynamicpropertiesofinhaledcorticosteroidsinrelationtoefficacyandsafety,RespiratoryMedicine1997;91(Supple.A),22-28020040060080010001200140016001800辅舒酮®布地奈德0204060辅舒酮®布地奈德糖皮质激素相对受体亲和力2糖皮质激素相对受体选择性1糖皮质激素受体结合半衰期3糖皮质激素受体结合肺/全身分布比16.0倍1.9倍10倍2.1倍氟替卡松（辅舒酮）疗效优于等效剂量级布地奈德BarnesNC,HallettC.&HarrisTAJ.ClinicalExperiencewithfluticasonepropionateinasthma:ameta-analysisofefficacyandsystemicactivitycomparedwithbudesonideandbecl